Pharmacological interventions for the prevention of contrast-induced acute kidney injury in high-risk adult patients undergoing coronary angiography: a systematic review and meta-analysis of randomised controlled trials.

Objective: Quantify the efficacy of strategies to prevent contrast-induced acute kidney injury (CI-AKI) in high-risk patients undergoing coronary angiography (CAG) with or without percutaneous coronary intervention (PCI). Background: CI-AKI remains a common problem. The renoprotective efficacy of existing pharmacological agents remains uncertain in high-risk populations. Methods: Systematic review and meta-analysis of randomised controlled trials (RCTs) to compare different strategies versus hydration in patients with chronic kidney disease (CKD) undergoing CAG±PCI. Primary outcome was incident CI-AKI. Fixed-effects meta-analyses estimated ORs, 95% CIs and heterogeneity. Results: Forty-eight RCTs were included. Seven pharmacological strategies were evaluated by multiple RCTs and 10 by one RCT each. These had varying risk of bias; >25% of trials were at high risk of performance bias. Five strategies significantly reduced the odds of CI-AKI: N-acetylcysteine (NAC) (27 trials, 5694 participants; OR=0.77, 95% CI 0.65 to 0.91, p=0.002, I2=36%), ascorbic acid (four trials, 759 participants; OR=0.59, 95% CI 0.39 to 0.89, p=0.01, I2=0%), statin (two trials, 3234 participants; OR=0.59, 95% CI 0.39 to 0.89, p=0.75, I2=0%), trimetazidine (two trials, 214 participants; OR=0.27, 95% CI 0.10 to 0.71, p=0.01, I2=0%) and nicorandil (two trials, 389 participants; OR=0.47, 95% CI 0.23 to 0.94, p=0.03, I2=52%). Theophylline had a similar, but non-significant, effect. A subgroup analysis found that the benefit of NAC was highest in patients requiring a high-contrast dose. Conclusions: Several drugs are renoprotective in patients with CKD undergoing CAG±PCI. The evidence is strongest for NAC. We recommend that NAC should be used when a high dose of contrast is anticipated. Trial registration number: PROSPERO registration CRD42014014704.Open Science Framework link: https://osf.io/vxg7d/?view_only=62bad0404b18405abd39ff2ead2575a8.

Vasopressors During Cardiopulmonary Resuscitation. A Network Meta-Analysis of Randomized Trials.

OBJECTIVES: Several randomized controlled trials have compared adrenaline (epinephrine) with alternative therapies in patients with cardiac arrest with conflicting results. Recent observational studies suggest that adrenaline might increase return of spontaneous circulation but worsen neurologic outcome. We systematically compared all the vasopressors tested in randomized controlled trials in adult cardiac arrest patients in order to identify the treatment associated with the highest rate of return of spontaneous circulation, survival, and good neurologic outcome. DESIGN: Network meta-analysis. PATIENTS: Adult patients undergoing cardiopulmonary resuscitation. INTERVENTIONS: PubMed, Embase, BioMed Central, and the Cochrane Central register were searched (up to April 1, 2017). We included all the randomized controlled trials comparing a vasopressor with any other therapy. A network meta-analysis with a frequentist approach was performed to identify the treatment associated with the highest likelihood of survival. MEASUREMENTS AND MAIN RESULTS: Twenty-eight studies randomizing 14,848 patients in 12 treatment groups were included. Only a combined treatment with adrenaline, vasopressin, and methylprednisolone was associated with increased likelihood of return of spontaneous circulation and survival with a good neurologic outcome compared with several other comparators, including adrenaline. Adrenaline alone was not associated with any significant difference in mortality and good neurologic outcome compared with any other comparator. CONCLUSIONS: In randomized controlled trials assessing vasopressors in adults with cardiac arrest, only a combination of adrenaline, vasopressin, and methylprednisolone was associated with improved survival with a good neurologic outcome compared with any other drug or placebo, particularly in in-hospital cardiac arrest. There was no significant randomized evidence to support neither discourage the use of adrenaline during cardiac arrest.

Propofol cardioplegia: A single-center, placebo-controlled, randomized controlled trial.

OBJECTIVES: Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is an effective treatment for coronary artery and aortic valve diseases. However, the myocardium sustains reperfusion injury after ischemic cardioplegic arrest. Our objective was to assess the benefits of supplementing cardioplegia solution with the general anesthetic propofol in patients undergoing either coronary artery bypass grafting (CABG) or aortic valve replacement (AVR). METHODS: A single-center, double-blind randomized controlled trial was carried out to compare cardioplegia solution supplemented with propofol (concentration 6 µg/mL) versus intralipid (placebo). The primary outcome was cardiac troponin T release over the first 48 hours after surgery. RESULTS: We recruited 101 participants (51 in the propofol group, 50 in the intralipid group); 61 underwent CABG and 40 underwent AVR. All participants were followed to 3 months. Cardiac troponin T release was on average 15% lower with propofol supplementation (geometric mean ratio, 0.85; 95% confidence interval [CI], 0.73-1.01; P = .051). There were no differences for CABG participants but propofol-supplemented participants undergoing AVR had poorer postoperative renal function (geometric mean ratio, 1.071; 95% CI, 1.019-1.125; P = .007), with a trend toward longer intensive care stay (median, 89.5 vs 47.0 hours; hazard ratio, 0.58; 95% CI, 0.31-1.09; P = .09) and fewer with perfect health (based on the EQ-5D health utility index) at 3 months (odds ratio, 0.26; 95% CI, 0.06-1.05; P = .058) compared with the intralipid group. Safety profiles were similar. There were no deaths. CONCLUSIONS: Propofol supplementation in cardioplegia appears to be cardioprotective. Its influence on early clinical outcomes may differ between CABG and AVR surgery. A larger, multicenter study is needed to confirm or refute these suggestions.

Warm-blood cardioplegia with low or high magnesium for coronary bypass surgery: a randomised controlled trial.

OBJECTIVE: Magnesium (Mg²âº) is cardioprotective and has been routinely used to supplement cardioplegic solutions during coronary artery bypass graft (CABG) surgery. However, there is no consensus about the Mg²âº concentration that should be used. The aim of this study was to compare the effects of intermittent antegrade warm-blood cardioplegia supplemented with either low- or high-concentration Mg²âº. METHODS: This study was a randomised controlled trial carried out in two cardiac surgery centres, Bristol, UK and Cuneo, Italy. Patients undergoing isolated CABG with cardiopulmonary bypass were eligible. Patients were randomised to receive warm-blood cardioplegia supplemented with 5 or 16 mmol l⁻¹ Mg². The primary outcome was postoperative atrial fibrillation. Secondary outcomes were serum biochemical markers (troponin I, Mg²âº, potassium, lactate and creatinine) and time-to-plegia arrest. Intra-operative and postoperative clinical outcomes were also recorded. RESULTS: Data from two centres for 691 patients (342 low and 349 high Mg²âº) were analysed. Baseline characteristics were similar for both groups. There was no significant difference in the frequency of postoperative atrial fibrillation in the high (32.8%) and low (32.0%) groups (risk ratio 1.03, 95% confidence interval, CI, 0.82-1.28). However, compared with the low group, troponin I release was 28% less (95% CI 55-94%, p=0.02) in the high-Mg²âº group. The 30-day mortality was 0.72% (n = 5); all deaths occurred in the high-Mg²âº group but there was no significant difference between the groups (p=0.06). Frequencies of other major complications were similar in the two groups. CONCLUSIONS: Warm-blood cardioplegia supplemented with 16 mmol l⁻¹ Mg²âº, compared with 5 mmol l⁻¹ Mg²âº, does not reduce the frequency of postoperative atrial fibrillation in patients undergoing CABG but may reduce cardiac injury. (This trial was registered as ISRCTN95530505.).

The administration of folic acid improves erectile function and reduces intracavernosal oxidative stress in the diabetic rabbit.

OBJECTIVE: To test the possibility that folic acid (FA) may be a means of treating erectile dysfunction (ED) in diabetes mellitus (DM), by studying the effect of FA administration to DM rabbits on cavernosal function and intrapenile oxidative stress. MATERIALS AND METHODS: To investigate the effect of administering FA to DM rabbits on erectile function and oxidative stress the formation of superoxide (O(2)(-)), 8-isoprostane F(2 alpha) (8-IPF(2 alpha)) and prostacyclin (as 6-keto-PGF(1 alpha)) were assessed, as well as carbachol- and electrical field stimulated (EFS) relaxation and p47(phox) content (active component of NADPH oxidase complex). Non-ketotic DM was induced in New Zealand rabbits with alloxan and FA administered orally daily for 1 month. Rabbits were killed, penises excised and segments prepared. These were mounted in an organ bath and relaxation elicited with carbachol or EFS. O(2)(-) release was measured spectrophotometrically, p47(phox) expression by Western blotting and 8-IPF(2 alpha) and 6-keto-PGF(1 alpha) formation by enzyme-linked immunosorbant assay. Blood was collected for measurement of homocysteine, red blood cell (RBC) folate and glucose. RESULTS: In cavernosal tissue from DM rabbits, carbachol-and EFS-induced relaxation was significantly impaired compared with the untreated controls. O(2)(-) release, p47(phox) expression and 8-IPF(2 alpha) formation were all enhanced and 6-keto-PGF(1 alpha) formation reduced compared with the controls. All these effects were reversed by FA. Plasma total homocysteine was reduced and RBC folate elevated. CONCLUSIONS: The administration of FA may constitute a strategy for reducing ED in patients with DM.

The administration of folic acid reduces intravascular oxidative stress in diabetic rabbits.

There is evidence that plasma homocysteine augments angiopathy in patients with diabetes mellitus. Although lowering homocysteine with folic acid improves endothelial function, the precise mechanisms underlying this effect are unknown. To study this area further, the effect of administration of folic acid to diabetic rabbits on intraaortic oxidative stress was studied by assessing the formation of superoxide (O(2)(-)), 8-isoprostane F(2alpha) (8-IPF(2alpha)), and prostacyclin (as 6-keto-PGF(1alpha)) as well as acetylcholine-stimulated relaxation and gp47(phox) content. Nonketotic diabetes mellitus was induced in New Zealand rabbits with alloxan, and low- and high-dose folic acid was administered daily for 1 month. Rabbits were killed, aortae were excised, and rings were prepared. Rings were mounted in an organ bath, and relaxation was elicited with acetylcholine. The O(2)(-) release was measured spectrophotometrically; the gp47(phox) expression, by Western blotting; and the 8-IPF(2alpha) and 6-keto-PGF(1alpha) formation, by enzyme-linked immunosorbent assay. Blood was collected for measurement of homocysteine, red blood cell folate, and glucose. In aortae from the diabetic rabbits, acetylcholine-induced relaxation was significantly impaired compared with that in untreated controls. The O(2)(-) release, p47(phox) expression, and 8-IPF(2alpha) formation were all enhanced and 6-keto-PGF(1alpha) formation was reduced compared with controls. All these effects were reversed by both low- and high-dose folic acid. Plasma total homocysteine was reduced by high-dose, but not low-dose, folic acid. Red blood cell folate was elevated in both groups. The improvement of endothelial function in patients receiving folic acid may be due to inhibition of nicotinamide adenine nucleotide phosphate oxidase (NADPH) oxidase expression and therefore conservation of nitric oxide and prostacyclin bioavailability, 2 vasculoprotective factors.

A randomized trial of tranexamic acid in combination with cell salvage plus a meta-analysis of randomized trials evaluating tranexamic acid in off-pump coronary artery bypass grafting.

OBJECTIVES: We sought to evaluate the effectiveness of tranexamic acid in off-pump coronary artery bypass grafting surgery, either when used in combination with mechanical cell salvage or when used alone. METHODS: One hundred patients were randomized to either 2 g of tranexamic acid as an intravenous bolus before sternotomy or to placebo. Intraoperative and postoperative cell salvage was used in all patients. The primary end point was early postoperative blood loss (within 4 hours). To evaluate the efficacy of tranexamic acid in isolation, we also performed a meta-analysis of 4 randomized trials identified from a systematic literature search. The primary end point of the meta-analysis was red cell transfusion. RESULTS: In our randomized trial patients in the tranexamic acid group had a significant reduction in early postoperative blood loss, (median difference, 50 mL; 95% confidence interval, 15-100 mL; P < .01); however, there was no reduction in the frequency of blood component transfusion. Patients in the placebo group received a significantly larger volume of autotransfused red cells (median difference, 120 mL; 95% confidence interval, 0-220 mL; P = .02). The meta-analysis demonstrated a significant reduction in red cell transfusions in patients receiving tranexamic acid compared with those receiving placebo (risk ratio, 0.48; 95% confidence interval, 0.24-0.97; P = .041). There was also a reduction in the frequency of any allogeneic blood component transfusion, as well as a highly significant reduction in postoperative blood loss, in patients receiving tranexamic acid (P < .001). CONCLUSIONS: Tranexamic acid reduces blood loss and transfusion requirements in off-pump coronary artery bypass grafting surgery. A reduction in allogeneic blood transfusion was not evident in the presence of perioperative cell salvage. These data support the routine use of tranexamic acid in off-pump coronary artery bypass grafting surgery.

Penicillamine administration reverses the inhibitory effect of hyperhomocysteinaemia on endothelium-dependent relaxation and superoxide formation in the aorta of the rabbit.

Although hyperhomocysteinaemia is a risk factor for cardiovascular disease, the mechanisms underlying this association have not been elucidated. It has been demonstrated, however, that copper augments the inhibitory effect of homocysteine on nitric oxide (NO)-mediated relaxation of the rat aorta through increased superoxide formation, which reacts with NO thereby reducing the bioavailability of NO. Since it follows that the administration of a copper chelator may blunt the pathogenic impact of hyperhomocysteinaemia, in vivo, the effect of penicillamine administration on NO-dependent relaxation and superoxide formation in the aortae of hyperhomocysteinaemic rabbits was studied. New Zealand White rabbits were fed a methionine-rich (20 g/kg chow) diet for 1 month+/-penicillamine administered orally (10 mg/kg/day) and aortic relaxation elicited with acetylcholine and superoxide measured. The role of NADPH oxidase was also studied using a range of inhibitors and western analysis of gp47(phox) (a catalytic subunit of NADPH oxidase). The methionine-rich diet markedly increased plasma total homocysteine levels. In hyperhomocysteinaemic rabbits there was a marked reduction of acetylcholine-stimulated relaxation and an increase in superoxide formation that were both inhibited with superoxide dismutase and apocynin, an NADPH oxidase inhibitor. Gp47(phox) expression was also increased in aortae from methionine fed rabbits. Penicillamine administration significantly reduced plasma total copper in methionine-fed rabbits compared to controls. Impaired acetylcholine-stimulated relaxation, increased superoxide formation and increased gp47(phox) expression in aortae from methionine-fed rabbits was reversed by penicillamine administration. These data indicate that hyperhomocysteinaemia augments the formation of arterial superoxide through an increase in NADPH oxidase expression/activity which in turn reduces NO bioavailability. Since these effects were reversed by penicillamine, these data consolidate the hypothesis that copper plays a role in mediating homocysteine-induced vasculopathy.

Magnesium-supplemented warm blood cardioplegia in patients undergoing coronary artery revascularization.

BACKGROUND: Although there is growing evidence to suggest that the administration of magnesium (Mg2+) to patients undergoing coronary artery bypass grafting (CABG) and to patients after myocardial infarction is beneficial, the addition of Mg2+ to cardioplegic solutions remains controversial. The aim of this study was to compare the effects of intermittent warm blood cardioplegia with and without Mg2+ supplementation on the early postoperative clinical outcomes in patients undergoing both elective or urgent CABG. METHODS: Four hundred patients undergoing CABG were prospectively randomized to receive either blood cardioplegia without Mg2+ (BC, n = 200) or supplemented with Mg2+ (BC-Mg2+, n = 200). Serial plasma Mg2+ concentrations were recorded at base line and postoperatively from days 1 to 4. RESULTS: Patient characteristics were similar and no significant differences were found in early mortality and morbidity in the two groups. Analysis of 178 patients undergoing urgent CABG for unstable symptoms (BC = 95, BC-Mg2+ = 83) demonstrated a significantly lower requirement for internal defibrillation and temporary epicardial pacing in the BC-Mg2+ group. Furthermore, there was a nearly twofold lower incidence of new postoperative atrial fibrillation in the BC-Mg2+ group compared with the BC group (19% versus 34%, p = 0.03). Postoperative plasma Mg2+ levels were consistently lower in those patients who developed new postoperative atrial fibrillation compared with those who did not (p = 0.05). CONCLUSIONS: The addition of Mg2+ to warm blood cardioplegia resulted in a lower incidence of intraoperative and postoperative arrhythmias in patients undergoing urgent CABG for unstable angina.